Regulations for In Vivo Radiopharmaceuticals Used for Diagnosis and Monitoring

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 315 and 601

[Docket No. 98N-0040]

RIN 0910-AB52

Regulations for In Vivo Radiopharmaceuticals Used for Diagnosis

and Monitoring

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing regulations

on the evaluation and approval of in vivo radiopharmaceuticals used in

the diagnosis and monitoring of diseases. FDA is issuing these

regulations in accordance with the Food and Drug Administration

Modernization Act of 1997 (the Modernization Act). These regulations

are intended to clarify existing regulations applicable to the approval

of radiopharmaceutical drugs and biologics under the Federal Food,

Drug, and Cosmetic Act (the act) and the Public Health Service Act (the

PHS Act).

EFFECTIVE DATE: Effective July 16, 1999.

FOR FURTHER INFORMATION CONTACT: Patricia Y. Love, Center for Drug

Evaluation and Research (HFD-160), Food and Drug Administration, 5600

Fishers Lane, Rockville, MD 20857, 301-827-7510; or George Q. Mills,

Center for Biologics Evaluation and Research (HFM-573), 1401 Rockville

Pike, Rockville, MD 20852-1448, 301-827-5097.

SUPPLEMENTARY INFORMATION:

I. Background

In the Federal Register of May 22, 1998 (63 FR 28301), FDA

published a proposed rule to implement section 122 of the Modernization

Act (Pub. L. 105-115). Section 122(a)(1) of the Modernization Act

directs FDA to issue proposed and final regulations on the approval of

radiopharmaceuticals intended for use in diagnosing or monitoring a

disease or a manifestation of disease in humans. The proposed

regulations apply to the approval of in vivo radiopharmaceuticals (both

drugs and biologics) used for diagnosis and monitoring.

The preamble to the proposed rule noted that FDA was in the process

of revising and supplementing its guidance to industry on product

approval and other matters related to the regulation of diagnostic

radiopharmaceutical drugs and biologics, and stated that such guidance

would address the application of the proposed rule. In the Federal

Register of October 14, 1998 (63 FR 55067), FDA announced the

availability of a draft guidance for industry entitled ``Developing

Medical Imaging Drugs and Biologics'' (medical imaging draft guidance).

The guidance, when completed, will assist developers of drug and

biological products used for medical imaging, including

radiopharmaceuticals used in disease diagnosis, in planning and

coordinating the clinical investigations of, and submitting various

types of applications for, such products. The guidance will also

provide information on how the agency will interpret and apply

provisions in the final rule on diagnostic radiopharmaceuticals.

In the Federal Register of January 5, 1999 (64 FR 457), FDA

reopened until February 12, 1999, the comment period on the medical

imaging draft guidance. In the Federal Register of February 16, 1999

(64 FR 7561), the agency further extended the comment period to April

14, 1999.

Several of the comments on the proposed rule on diagnostic

radiopharmaceuticals addressed issues that are also relevant to the

medical imaging draft guidance. In FDA's responses to the comments set

forth in section III of this document, the agency refers to relevant

portions of the draft guidance that interpret and apply provisions of

the regulations on diagnostic radiopharmaceuticals. In finalizing the

medical imaging guidance, FDA will carefully consider all comments

received on the proposed rule that are relevant to issues addressed in

the draft guidance.

II. Highlights of the Final Rule

In accordance with section 122 of the Modernization Act, the final

rule adds new regulations pertaining to the review and approval of in

vivo radiopharmaceuticals used for diagnosis and monitoring. The new

regulations in part 315 (21 CFR part 315) and part 601 (21 CFR part

601) (Secs. 601.30 through 601.35)) complement and clarify existing

regulations on the approval of drugs and biologics in part 314 (21 CFR

part 314) and part 601, respectively. The regulations include a

definition of diagnostic radiopharmaceuticals and

[[Page 26658]]

provisions that address the following aspects of these products: (1)

General factors to be considered in determining safety and

effectiveness, (2) proposed indications for use, (3) evaluation of

effectiveness, and (4) evaluation of safety.

FDA revised the proposed rule in response to comments received on

the proposal. Proposed Secs. 315.4(b) and 601.33(b) were revised to

clarify that where a diagnostic radiopharmaceutical is not intended to

provide disease-specific information, the proposed indications for use

may refer to a biochemical, physiological, anatomical, or pathological

process or to more than one disease or condition.

FDA also revised the provisions on the evaluation of effectiveness

of a diagnostic radiopharmaceutical. The agency revised proposed

Secs. 315.5(a)(1) and (a)(2) and 601.34(a)(1) and (a)(2) to state that

claims of structure delineation and of functional, physiological, or

biochemical assessment must be demonstrated in a defined clinical

setting that is appropriate for the intended clinical benefit (as is

the case with claims of: (1) Disease or pathology detection or

assessment and (2) diagnostic or therapeutic patient management). In

addition, FDA revised Secs. 315.5(a)(1) and 601.34(a)(1) to state that

a structure delineation claim involves an ability ``to locate

anatomical structures and to characterize their anatomy,'' rather than

an ability ``to locate and characterize normal anatomical structures.''

FDA also revised the provisions on the evaluation of the safety of

a diagnostic radiopharmaceutical. Proposed Secs. 315.6(a) and 601.35(a)

were revised to add to the factors that FDA will consider in assessing

the safety of a diagnostic radiopharmaceutical the results of any

previous human experience with the carrier or ligand of a

radiopharmaceutical when the same chemical entity as the carrier or

ligand has been used in a previously studied product. Similarly, the

agency revised Secs. 315.6(c)(2) and 601.35(c)(2) to specify that the

amount of new safety data required to be submitted for a particular

diagnostic radiopharmaceutical will depend on the characteristics of

the product and available information on the safety of not only the

diagnostic radiopharmaceutical itself but also its carrier or ligand.

These sections were also revised to state that the safety information

that FDA may require may include the results of clinical studies, in

addition to the results of preclinical studies. Additionally, these

sections were revised to clarify that the agency will establish

categories of diagnostic radiopharmaceuticals based on defined risk

characteristics and, upon reviewing a particular diagnostic

radiopharmaceutical's relevant product characteristics and safety

information, will place the radiopharmaceutical into the appropriate

safety risk category. FDA also deleted the requirements in proposed

Secs. 315.6(d) and 601.35(d) on the tests that must be included in a

radiation dosimetry evaluation of a diagnostic radiopharmaceutical

(i.e., dosimetry to total body, to specific organs or tissues, and, as

appropriate, to target organs or tissues) in favor of addressing this

matter in the medical imaging guidance.

Finally, FDA made minor editorial changes to the final rule in

response to the President's June 1, 1998, memorandum on plain language

in government writing.

III. Responses to Comments on the Proposed Rule

FDA received nine written comments on the proposed rule. The

comments were submitted by manufacturers, trade associations,

universities, and a health care organization.

A. General Responses

1. One comment expressed support for the intent of the proposed

regulations, but it questioned how FDA could develop acceptable

indications, as well as safety and effectiveness criteria for

radiopharmaceuticals, without doing the same for all diagnostic drugs

and biologics. The comment maintained that while radiopharmaceuticals

may be a unique ``chemical'' class, they are part of the

``therapeutic'' class of diagnostic agents used for medical imaging.

The comment further contended that because the proposed regulations on

diagnostic radiopharmaceuticals were designed to clarify FDA's

expectations and might reduce the cost of developing these products,

adoption of these regulations would create a competitive disadvantage

for companies developing nonradiopharmaceutical products for the same

indications and efficacy endpoints.

Section 122(a)(1) of the Modernization Act directs FDA to develop

regulations specifically governing the approval of diagnostic

radiopharmaceuticals. It does not direct the agency to establish new

approval procedures that would apply to all in vivo diagnostic agents,

including radiopharmaceuticals and contrast agents. Consequently, as

stated in Secs. 315.1 and 601.30, the final rule applies to

radiopharmaceuticals intended for in vivo administration for diagnostic

and monitoring use; it does not apply to radiopharmaceuticals intended

for therapeutic use or to nonradiopharmaceutical products. FDA will

consider whether it should develop similar regulations for

nonradiopharmaceutical diagnostic agents in the future.

However, FDA agrees with the comment that there are common

principles in developing diagnostic imaging products. FDA's medical

imaging draft guidance addresses such matters as conducting clinical

studies and submitting applications for all medical imaging drugs and

biologics, not just diagnostic radiopharmaceuticals. In doing so, the

draft guidance elaborates on the concepts set forth in the proposed

rule on diagnostic radiopharmaceuticals. Consequently, although the

final rule applies only to diagnostic radiopharmaceuticals, FDA is

proposing in the medical imaging draft guidance that the principles set

forth in this final rule should apply to all medical imaging drugs and

biologics, including contrast agents.

B. Definition

Proposed Secs. 315.2 and 601.31 defined a diagnostic

radiopharmaceutical as an article that is intended for use in the

diagnosis or monitoring of a human disease or manifestation of disease

and that exhibits spontaneous disintegration of unstable nuclei with

the emission of nuclear particles or photons. The definition also

included any nonradioactive reagent kit or nuclide generator that is

intended to be used in the preparation of a previously defined article.

2. One comment, noting that three of the four indication categories

under proposed Secs. 315.4 and 601.33 did not include the word

``diagnostic,'' asked whether the regulations should state a definition

of ``radiopharmaceutical'' rather than ``diagnostic

radiopharmaceutical'' to be consistent with section 122 of the

Modernization Act.

Although section 122(b) of the Modernization Act includes a

definition of ``radiopharmaceutical'' rather than ``diagnostic

radiopharmaceutical,'' the term applies only to radiopharmaceuticals

``intended for use in the diagnosis or monitoring of a disease or a

manifestation of a disease in humans * * *.'' Consequently, FDA states

in Secs. 315.1 and 601.30 that the regulations in part 315 and part

601, subpart D, respectively, apply to radiopharmaceuticals intended

for diagnostic and monitoring use and not to radiopharmaceuticals

intended for therapeutic purposes. FDA believes that

[[Page 26659]]

the definition and use of the term ``diagnostic radiopharmaceutical''

in these regulations are consistent with the Modernization Act and the

scope of these regulations. Although three of the four categories of

indications do not include the word ``diagnostic,'' it is clear from

the context of the regulations that each of the categories applies to

diagnostic or monitoring indications and not to therapeutic

indications.

3. Two comments asked that FDA clarify a statement in the preamble

to the proposed rule (63 FR 28301 at 28303) that the definition of

diagnostic radiopharmaceutical includes articles that exhibit

spontaneous disintegration leading to reconstruction of unstable nuclei

and the subsequent emission of nuclear particles or photons.

Proposed Secs. 315.2 and 601.31 defined a diagnostic

radiopharmaceutical as an article ``that exhibits spontaneous

disintegration of unstable nuclei with the emission of nuclear

particles or photons * * *.'' This definition is identical to the

definition of ``radiopharmaceutical'' in section 122(b) of the

Modernization Act. FDA was concerned that this definition might be

interpreted as excluding an article that exhibits spontaneous

disintegration leading to the reconstruction of unstable nuclei and the

subsequent emission of nuclear particles or photons (i.e., the electron

capture process of decay). Therefore, the agency stated in the preamble

that it interprets the definition of ``radiopharmaceutical'' in section

122(b) of the Modernization Act and ``diagnostic radiopharmaceutical''

in proposed Secs. 315.2 and 601.31 as including such an article. This

statement was intended to clarify that diagnostic radiopharmaceuticals

include articles with unstable nuclei that do not initiate decay by

spontaneous disintegration but by spontaneous incorporation of an

electron into the nucleus, bonding with a proton to form a neutron.

This is followed by neutrino emission from the nucleus and both x-ray

and Auger electron emissions from the electron shells. Iodine-123 is an

example of a radionuclide that decays in this manner.

C. Indications

Proposed Secs. 315.4(a) and 601.33(a) specified the following

categories of indications for which FDA may approve a diagnostic

radiopharmaceutical: (1) Structure delineation; (2) functional,

physiological, or biochemical assessment; (3) disease or pathology

detection or assessment; and (4) diagnostic or therapeutic patient

management.

4. One comment, referring to examples of structural delineation and

functional/physiological/biochemical assessment indications provided in

the preamble to the proposed rule, requested that FDA provide examples

of actual claim language and primary endpoints of adequate and well

controlled clinical trials for drugs with such types of indications.

FDA does not believe that it would be appropriate to suggest

potential language for indications for use or primary clinical

endpoints outside of the context of evaluating a specific diagnostic

radiopharmaceutical for a desired indication. However, the medical

imaging draft guidance provides examples of products with such

categories of indications and discusses the kinds of claim statements

that may be permitted in promotional materials for such products. The

draft guidance also provides examples of the types of endpoints that

are appropriate for clinical studies on medical imaging drugs and

biologics.

5. One comment stated that the distinction between the disease

detection and patient management categories of indications in proposed

Secs. 315.4(a)(3) and (a)(4) and 601.33(a)(3) and (a)(4) was vague and

asked whether the former category allowed for use of the phrase ``as an

aid in the diagnosis of [a specific disease].'' The comment further

stated that the difference between the two categories appeared to be

related to the ability to provide diagnostic information and/or lead to

a decision on patient management. However, the comment found it

difficult to understand how a diagnostic radiopharmaceutical could

characterize a specific disease as described in the preamble (63 FR

28301 at 28303) and not be of diagnostic value (i.e., fall within the

diagnostic or therapeutic patient management indication category).

FDA agrees that there is a need to further clarify the distinction

between the disease or pathology detection and assessment indication

category and the diagnostic or therapeutic patient management

indication category. A disease or pathology detection or assessment

claim is established by demonstrating that a diagnostic

radiopharmaceutical provides clinically useful information that can

assist in the detection, localization, or characterization of a

specific disease or pathological state in a defined clinical setting.

However, the way that the information affects patient management is

implied and may not be directly studied. The phrases ``as an aid in''

or ``as an adjunct to'' may be appropriate for this type of indication.

On the other hand, a diagnostic or therapeutic patient management claim

is established by explicitly demonstrating a radiopharmaceutical's

ability to provide imaging or related information that leads directly

to an appropriate diagnostic or therapeutic management decision for

patients in a defined clinical setting. FDA will revise the medical

imaging draft guidance to further distinguish disease/pathology

detection and assessment indications from patient management

indications.

6. One comment, stating that reliance on patient management for a

diagnostic claim might be unfounded, asked what indication language FDA

might approve for a diagnostic radiopharmaceutical if there were no

approved therapy for treating a specific disease.

A diagnostic or patient management decision need not necessarily

relate to the use of an approved drug product or therapy. Therefore,

the absence of an approved therapy for a particular disease would not

necessarily mean that FDA would not approve a diagnostic

radiopharmaceutical with an indication for diagnostic or therapeutic

management of patients with that disease. However, the applicant would

need to demonstrate that its product has some clinical value. For

example, in a situation in which two disorders are difficult to

distinguish but a treatment exists for only one of the two, a

radiopharmaceutical might be used to distinguish between the two

disorders, thereby directly affecting subsequent patient management. In

addition, a diagnostic radiopharmaceutical could have clinical

usefulness in providing disease progression information about an

untreatable disease; a patient management claim might be appropriate if

such information were shown to directly affect some aspect of patient

management (e.g., symptomatic treatment, avoidance of unnecessary

treatment). As with all diagnostic radiopharmaceuticals for which a

patient management indication is sought, FDA would need to determine

whether the proposed clinical studies on the product included endpoints

for assessing the appropriateness of patient management or clinical

outcomes. The medical imaging draft guidance provides further

clarification on the indications that may be appropriate for a

diagnostic radiopharmaceutical under these circumstances.

7. Two comments expressed concern that FDA might narrowly interpret

the diagnostic or therapeutic patient management indication category,

noting that the two examples provided in the preamble involved

indications dealing

[[Page 26660]]

with initial patient management, i.e., deciding therapeutic course. The

comments sought confirmation that this indication category would

include diagnostic radiopharmaceuticals used in followup patient

management, i.e., monitoring response to therapy.

Although the two examples in the proposed rule related to initial

patient management rather than monitoring response to therapy, FDA

affirms that the diagnostic or therapeutic patient management

indication category includes drugs used to monitor patient response to

therapy if the response to therapy has direct implications for

subsequent patient management. Possible diagnostic or therapeutic

patient management indications might include diagnostic evaluation, use

of a nonregulated therapy such as surgery, and other significant

aspects of how a patient is treated. For example, a diagnostic

radiopharmaceutical might be used to evaluate whether therapy for a

malignancy is causing tumor regression if that information directly

affects subsequent patient management decisions. A patient management

indication also might be appropriate for a radiopharmaceutical that

provides a convenient, well tolerated, accurate test that has been

shown to effectively replace a more cumbersome or risky standard

battery of tests, regardless of the availability of therapy.

8. Proposed Secs. 315.4(b) and 601.33(b) stated that where a

diagnostic radiopharmaceutical is not intended to provide disease-

specific information, the proposed indications for use might refer to a

process or to more than one disease or condition. One comment stated

that this provision properly implements the special rule in section

122(a)(2) of the Modernization Act that a radiopharmaceutical may be

approved for indications referring to manifestations of disease (such

as biochemical, physiological, anatomical, or pathological processes)

common to, or present in, one or more disease states. However, the

comment asked that the phrase ``biochemical, physiological, anatomical,

or pathological'' be added before the word ``process'' to eliminate the

possibility that ``process'' might be construed as referring to a

diagnostic procedure.

FDA agrees with the comment and has revised Secs. 315.4(b) and

601.33(b) accordingly.

D. Evaluation of Effectiveness

In proposed Secs. 315.5 and 601.34, FDA set forth the specific

criteria that the agency would use to evaluate the effectiveness of a

diagnostic radiopharmaceutical. The proposed rule stated that

effectiveness would be assessed by evaluating the ability of the

diagnostic radiopharmaceutical to provide useful clinical information

related to the proposed indications for use. The method of this

evaluation would vary depending on the proposed indication.

9. One comment maintained that the proposed rule should have

detailed the differences between diagnostic radiopharmaceuticals and

conventional, nonradioactive drugs as a basis for a different

regulatory treatment. For example, the comment stated that adequate and

well controlled investigations are not applicable to diagnostic

radiopharmaceuticals and that specific studies involving each

potentially applicable disease state should not be required for such

drugs. The comment argued that ``proof of principle'' is all that has

been required by the Atomic Energy Commission (AEC) and that use of

this standard would be a good way to implement the requirements of the

Modernization Act.

Section 122(a)(1)(A) of the Modernization Act directs FDA to

develop regulations for determining the safety and effectiveness of

diagnostic radiopharmaceuticals under section 505 of the act (21 U.S.C.

355) and section 351 of the PHS Act (42 U.S.C. 262); it does not exempt

diagnostic radiopharmaceuticals from the requirements of those

statutory provisions. Under section 505(d)(5) of the act, FDA may

refuse to approve a new drug application (NDA) if, among other things,

there is a lack of substantial evidence that the drug will have the

effect it purports or is represented to have under the conditions of

use in its proposed labeling. ``Substantial evidence'' is defined as

adequate and well controlled investigations, including clinical

investigations, by qualified experts, on the basis of which such

experts may fairly and responsibly conclude that the drug will have its

intended effect. Under section 351 of the PHS Act, FDA approves a

biologics license application (BLA) on, among other things, a

demonstration that the biological product is safe, pure, and potent.

Potency has long been interpreted to include effectiveness ``as

indicated by appropriate laboratory tests or by adequately controlled

clinical data obtained through the administration of the product in the

manner intended'' (21 CFR 600.3(s)). FDA believes that the standard of

substantial evidence is appropriate for use in evaluating the

sufficiency of evidence of effectiveness submitted in a BLA (see FDA's

guidance for industry entitled ``Providing Clinical Evidence of

Effectiveness for Human Drugs and Biological Products,'' May 1998). For

these reasons, FDA may not establish regulations for diagnostic

radiopharmaceuticals that exempt such drugs and biologics from the

statutory requirements.

The ``proof of principle'' concept noted by the comment was used by

the Nuclear Regulatory Commission (NRC), the successor agency to the

AEC. The NRC licenses persons who use nuclear materials. NRC standards

are directed exclusively at radiological health and safety. The NRC

focuses on ensuring an adequate level of radiation protection without

regard to whether a radiopharmaceutical actually works. Because it is

FDA's statutory responsibility to determine the safety and

effectiveness of drug products, the NRC's standards are not relevant to

the approval of diagnostic radiopharmaceuticals under the act. Proof of

principle, e.g., the metabolic, pharmacokinetic, and pharmacological

database on a diagnostic radiopharmaceutical, is only part of the drug

development process. This information alone is insufficient to meet the

requirements in the act and in FDA regulations on safety and

effectiveness and on product labeling statements regarding such matters

as safe use, the adverse event profile, and clinical use information.

10. One comment maintained that because statements in the preamble

describing the structure delineation and functional/physiological/

biochemical assessment indication categories do not mention clinical

benefit, unlike the descriptions of the other two categories, FDA

should state that a demonstration of ``traditional'' clinical utility

or benefit is not required for diagnostic radiopharmaceuticals with

these types of indications. However, the comment noted that this

interpretation contradicted the statement in proposed Secs. 315.5(a)

and 601.34(a) that the effectiveness of a diagnostic

radiopharmaceutical is assessed by evaluating its ability to provide

``useful clinical information'' concerning its proposed indications.

The comment stated that it was unclear how one could provide useful

clinical information related to a proposed indication for use that

would not be of diagnostic or patient management value. Alternatively,

the comment asked that FDA provide an example of a drug that

demonstrates clinical utility but does not aid in diagnosis or

contribute to patient management.

Although not explicitly stated in the preamble discussion on

indication categories, a demonstration of clinical

[[Page 26661]]

benefit, i.e., ability to provide useful clinical information related

to proposed indications for use, is required for approval of all types

of diagnostic radiopharmaceuticals under Secs. 315.5(a) and 601.34(a).

The indication categories are intended to describe the types of

clinically useful information that could be derived from an imaging

study, and the type of indication for a particular product is related

to the type of clinical trial designs that are used in the clinical

studies. The draft medical imaging guidance further addresses these

matters.

It is indeed possible for a diagnostic radiopharmaceutical to

provide useful clinical information without directly being effective

for detecting or assessing a disease or aiding patient management. For

example, a diagnostic radiopharmaceutical might be used to locate and

outline a normal parathyroid gland; while this information might not

directly result in disease diagnosis and might not be demonstrated to

improve patient management, it could indirectly assist a physician in

planning and performing surgery to remove a mass in the thyroid gland.

11. Proposed Secs. 315.5(a)(1) through (a)(5) and 601.34(a)(1)

through (a)(5) set forth the criteria for demonstrating effectiveness

with respect to particular categories of indications. A structure

delineation claim would be established by demonstrating the ability of

the diagnostic radiopharmaceutical to locate and characterize normal

anatomical structures. A claim of functional, physiological, or

biochemical assessment would be established by demonstrating reliable

measurement of functions or physiological, biochemical, or molecular

processes. A claim of disease or pathology detection or assessment

would be established by demonstrating in a defined clinical setting

that the diagnostic radiopharmaceutical has sufficient accuracy in

identifying or characterizing a disease or pathology. A claim of

diagnostic or therapeutic patient management would be established by

demonstrating in a defined clinical setting that the test is useful in

diagnostic or therapeutic management of patients.

One comment suggested that the word ``normal'' be deleted from

proposed Secs. 315.5(a)(1) and 601.34(a)(1) because

radiopharmaceuticals with structure delineation indications are used to

locate and characterize structures that may be normal or abnormal, and

in some cases they may be used to help determine the abnormal

appearance of a structure.

FDA agrees to delete the word ``normal'' from Secs. 315.5(a)(1) and

601.34(a)(1) because a structure delineation claim may be appropriate

for a diagnostic radiopharmaceutical that is used to determine the

anatomical appearance of a structure even when the anatomy is abnormal.

However, to clarify FDA's intent as to what is needed to demonstrate a

structure delineation claim, the agency is further revising these

provisions to state that a claim of structure delineation is

established by demonstrating the ability to locate anatomical

structures and to characterize their anatomy. FDA recognizes the need

to clarify when a structure delineation claim is appropriate rather

than a claim in one of the other indication categories. The agency will

consider revising the medical imaging draft guidance to further explain

the scope of permissible structure delineation claims.

12. One comment maintained that the information provided by

radiopharmaceuticals with functional, physiological, or biochemical

assessment indications may be either quantitative, semiquantitative, or

qualitative. To prevent Secs. 315.5(a)(2) and 601.34(a)(2) from being

interpreted as permitting only quantitative measurement of function or

process in establishing a functional, physiological, or biochemical

assessment claim, the comment requested that the phrase ``quantitative,

semi-quantitative, or qualitative'' be added before the word

``measurement.''

FDA agrees with the comment that a diagnostic radiopharmaceutical

with a functional, physiological, or biochemical assessment indication

may be established through either a quantitative, semi-quantitative, or

qualitative measurement of a function or process. However, the agency

concludes that it is not necessary to revise Secs. 315.5(a)(2) and

601.34(a)(2) as requested because these provisions do not require any

specific type of measurement.

13. One comment asked FDA to confirm that claims involving

structure delineation or physiological assessment would not require

evaluation in a defined clinical setting under proposed

Secs. 315.5(a)(1) and (a)(2) and 601.34(a)(1) and (a)(2), as would be

required for disease detection and patient management claims under

proposed Secs. 315.5(a)(3) and (a)(4) and 601.34(a)(3) and (a)(4). In

particular, the comment asked whether, if a sponsor could demonstrate

unequivocally a diagnostic radiopharmaceutical's ability to quantitate

nucleic acid synthesis (one of the preamble's examples of a biochemical

assessment indication), FDA would require the sponsor to demonstrate

such effectiveness in a clinically relevant setting or patient

population.

FDA believes that to demonstrate that a diagnostic

radiopharmaceutical has the ability to provide useful clinical

information in accordance with Secs. 315.5(a) and 601.34(a), the drug

must be evaluated in a defined clinical setting, regardless of its

proposed indication. Consequently, FDA has revised Secs. 315.5(a)(1)

and (a)(2) and 601.34(a)(1) and (a)(2) to specify that structure

delineation and functional, physiological, or biochemical assessment

claims, like disease detection and patient management claims, must be

demonstrated in a defined clinical setting. The medical imaging draft

guidance provides further discussion and explanation of the defined

clinical setting. Claims involving structure delineation or

physiological assessment must be evaluated under a clinical protocol

and require a population from a clinically relevant setting. Regarding

the hypothetical situation posed by the comment, even if a sponsor were

able to demonstrate unequivocally that a diagnostic radiopharmaceutical

was able to quantitate nucleic acid synthesis, the sponsor would have

to demonstrate the usefulness of the imaging information in a

clinically relevant setting. The clinical setting might be broad,

demonstrating the common value of nucleic acid synthesis.

Alternatively, the clinical studies might involve patients with a need

for a particular type of evaluation (e.g., radionuclide ejection

fraction) regardless of the underlying disease.

14. Under proposed Secs. 315.5(b) and 601.34(b), the accuracy and

usefulness of diagnostic information provided by a diagnostic

radiopharmaceutical would be determined by comparison with a reliable

assessment of actual clinical status, which could be provided by a

diagnostic standard or standards of demonstrated accuracy. One comment

maintained that these sections should be deleted because the act does

not require either accuracy or usefulness. The comment stated that

practitioners determine the accuracy and usefulness of a diagnostic

radiopharmaceutical and that this information may be found in peer-

reviewed literature, in the United States Pharmacopoeia Drug

Information, and at professional and continuing medical education

meetings. The comment added that accuracy and usefulness were never a

part of the AEC process.

[[Page 26662]]

FDA declines the request to delete Secs. 315.5(b) and 601.34(b).

Although section 505(d) of the act and section 351 of the PHS Act do

not specifically require that a new drug or biologic be shown to be

``accurate'' and ``useful,'' they do authorize FDA, as noted

previously, to refuse to approve an application if there is a lack of

substantial evidence that the product will have the effect it purports

or is represented to have under the proposed conditions of use, based

on an evaluation of well controlled clinical trials on the product. The

statistical assessment of such trials includes accuracy; the clinical

assessment considers the usefulness of the diagnostic information in

the studied clinical setting and the proposed indication. FDA

acknowledges that in the practice of medicine physicians may obtain

information about a particular diagnostic radiopharmaceutical from

numerous sources, including the published literature, and they may make

diagnosis and treatment decisions on the basis of such information.

Such literature typically becomes available after a product is

marketed. However, a diagnostic radiopharmaceutical may not be marketed

unless the agency determines, on the basis of data from clinical trials

and other information, that the drug is safe and effective under

section 505 of the act or section 351 of the PHS Act, and that

determination must include the accuracy and usefulness of the product.

E. Evaluation of Safety

Proposed Secs. 315.6(a) and 601.35(a) listed the factors that FDA

would consider in assessing the safety of a diagnostic

radiopharmaceutical. These factors include the following: The radiation

dose; the pharmacology and toxicology of the radiopharmaceutical

(including any radionuclide, carrier, or ligand); the risks of an

incorrect diagnostic determination; the drug's adverse reaction

profile; and results of human experience with the drug for other uses.

15. One comment maintained that there is no ``pharmacology and

toxicology of the radiopharmaceutical, including any radionuclide,

carrier, or ligand,'' as stated in proposed Secs. 315.6(a) and

601.35(a).

FDA disagrees with the comment. The agency is aware of specific

diagnostic radiopharmaceuticals, ligands, and carriers that have been

shown to have a pharmacological or toxicological effect on the human

body. For example, biological antibodies used in radiopharmaceuticals

have demonstrated pharmacological and immunologic activity. In

addition, as the development of radiopharmaceuticals increasingly

focuses on receptors and metabolic processes, ligands (either

synthesized peptides or antibodies) could have agonist or antagonist

activity at nanomolar levels.

16. One comment asked why the safety of a diagnostic

radiopharmaceutical might relate to the pharmacological action of its

ligand rather than an observed adverse event, suggesting that a

deleterious pharmacological action would be manifested as an adverse

event.

The pharmacological action of a diagnostic radiopharmaceutical's

ligand directly affects the sponsor's plan for detecting adverse events

associated with the administration of a radiopharmaceutical. Without

knowledge of the pharmacological action, the sponsor's selected time

intervals for monitoring (e.g., immediate reactions, 7- to 10-day

reactions, 3- to 6-month reactions) may not allow for observation,

detection, and reporting of adverse events that occur during other time

intervals. Also, some adverse events are not reported by patients and

may not be suggested by animal studies; they may be identified only by

physical examination (e.g., detection of nystagmus by cranial nerve

examination). In addition, if the pharmacological action of the ligand

is not known, the sponsor may not determine and use the appropriate

modality (e.g., clinical evaluation, laboratory assessment,

radiographic imaging) to monitor adverse events. For example, in a

radiopharmaceutical that binds irreversibly to activated platelet

receptors, a pharmacology evaluation would demonstrate an inhibition of

platelet aggregation. Subsequent clinical studies should evaluate the

bleeding time and potential drug interaction with treatments that

prolong bleeding. Therefore, it is appropriate to include both the

pharmacology and toxicology of a diagnostic radiopharmaceutical

(including any radionuclide, carrier, or ligand) as well as the drug's

adverse reaction profile as separate factors to consider in evaluating

the safety of a diagnostic radiopharmaceutical.

17. One comment stated that FDA should delete the risks of an

incorrect diagnostic determination as a factor in assessing the safety

of a diagnostic radiopharmaceutical. The comment maintained that such

risks depend on physician competence, patient cooperation, equipment

quality, and other factors that are not characteristics of a diagnostic

radiopharmaceutical, and that such a provision does not appear in the

act.

FDA disagrees with the proposed deletion. The risk of an incorrect

diagnostic determination is an independent factor to be considered in

evaluating the safety of a diagnostic radiopharmaceutical under section

505 of the act or section 351 of the PHS Act. For example, a new

diagnostic radiopharmaceutical might produce images and clinical

information that require additional physician knowledge and competence

for adequate interpretation or that might suggest an incorrect

diagnosis even though interpreted by a well trained physician.

Misinterpretation of the diagnostic images in such circumstances might

pose a significant threat to the health of patients.

18. One comment stated that a diagnostic radiopharmaceutical's

adverse reaction profile should not be considered because it is

generally nonexistent, nonspecific, or trivial.

FDA disagrees with the comment. It is possible for a diagnostic

radiopharmaceutical to have a specific and significant adverse reaction

profile. Examples are the development of angina after the injection of

a synthetic radiopharmaceutical to evaluate myocardial perfusion and

the immune system response to the administration of a radiolabeled

small peptide or antibody. The production of a human antimurine

antibody has been demonstrated in response to both first administration

as well as multiple administrations of a murine antibody. The

production of the immune response to the administration of the murine

antibody has elicited life-threatening anaphylactoid responses.

Therefore, a diagnostic radiopharmaceutical's adverse reaction profile

is a relevant factor to consider in assessing the drug's safety.

19. Two comments addressed the proposed safety assessment factor

concerning ``the results of human experience with the

radiopharmaceutical for other uses.'' One comment found this factor to

be confusing and asked that FDA explain the phrase and provide some

examples. Another comment agreed with the proposed rule that, when an

applicant is seeking approval for a new indication for a previously

approved radiopharmaceutical, the clinical data in the approved

application and postmarketing experience with that product should be

considered in assessing the safety of that radiopharmaceutical for the

proposed new use. However, the comment maintained that human safety

data on a

[[Page 26663]]

ligand or carrier used in a radiopharmaceutical may be important even

though the radiopharmaceutical has not been previously approved. The

comment stated that the radionuclide component of a radiopharmaceutical

may have a long history of use in other radiopharmaceuticals and that

most radiopharmaceutical issues (other than radiation dosimetry issues)

will arise from the potential pharmacological or toxicological

properties of the compound used in the carrier or ligand, about which

there may be relevant safety information from use in marketed products.

Therefore, the comment recommended that the following factor be added

to the end of Secs. 315.6(a) and 601.35(a):

the results of previous human experience with the ligand or

carrier component (if any) of the radiopharmaceutical where

essentially the same chemical entity as the ligand or carrier has

been used in a previously approved product (e.g., as the ligand or

carrier in another diagnostic or therapeutic radiopharmaceutical or

as the active ingredient in a nonradioactive product for therapeutic

use).

FDA believes that human experience with a diagnostic

radiopharmaceutical for previously approved uses (or even uses that

have been studied but are unapproved) could provide important

information about the safety of that radiopharmaceutical for a proposed

new use. For example, the agency would review the safety experience of

technetium-99m (Tc-99m) pyrophosphate used in bone imaging if a sponsor

submitted an application for approval of that drug for a new

indication, such as imaging of myocardial infarction. FDA agrees with

the comment that the results of any human experience with the carrier

or ligand of a diagnostic radiopharmaceutical, as used in a previously

studied product (either as a ligand or carrier in a radiopharmaceutical

or as an active ingredient in a nonradioactive drug product), should be

considered in assessing the safety of a diagnostic radiopharmaceutical.

Therefore, FDA has revised Secs. 315.6(a) and 601.35(a) accordingly.

However, the agency believes that this human experience must involve

the exact chemical entity as the carrier or ligand of the diagnostic

radiopharmaceutical undergoing safety assessment, rather than

``essentially the same chemical entity'' as the comment recommended.

(For purposes of part 315 and subpart D of part 601, the terms

``carrier'' and ``ligand'' collectively refer to the entire

nonradionuclidic portion of a diagnostic radiopharmaceutical.)

20. Proposed Secs. 315.6(b) and 601.35(b) stated that the

assessment of a diagnostic radiopharmaceutical's adverse reaction

profile includes, but is not limited to, an evaluation of the potential

of the drug (including its carrier or ligand) to elicit allergic or

hypersensitivity responses, immunologic responses, changes in the

physiologic or biochemical function of target and nontarget tissues,

and clinically detectable signs or symptoms. One comment stated that

although allergic and immunologic responses may be an issue with

foreign proteins, a determination of antibody production in a small

number of subjects would be enough to determine whether such responses

are common.

FDA disagrees with the comment. The agency believes that there

should be adequate clinical experience with a diagnostic

radiopharmaceutical to identify uncommon as well as common allergic and

immunologic responses to the radiopharmaceutical. Data on a small

number of subjects generally are insufficient to identify an uncommon

but potentially life-threatening adverse reaction.

21. One comment recommended adding the words ``Clinically

significant'' before ``Changes in the physiologic or biochemical

function of the target and nontarget tissues'' in proposed

Secs. 315.6(b)(3) and 601.35(b)(3) because such changes are relevant to

assessing a diagnostic radiopharmaceutical's adverse reaction profile

only when they are clinically significant. As an example, the comment

stated that the process by which a radiopharmaceutical binds to an

intended receptor on a cell surface might be regarded as a change in

the biochemical function of the target tissue even though the change

has no potential to adversely affect safety and has no other clinical

significance. The comment contended that its suggested revision would

be consistent with a statement in the agency's medical imaging draft

guidance (i.e., that localization of a medical imaging drug in a target

organ or tissue is not considered to have a biological effect unless it

produces demonstrable perturbation).

FDA declines to revise Secs. 315.6(b)(3) and 601.35(b)(3) as

recommended. The agency believes that the potential of a product to

change the physiologic or biochemical function of target and nontarget

tissues should be evaluated. The clinical significance of any detected

functional change should be assessed. If the functional change has

little or no clinical significance, it likely will not affect the

diagnostic radiopharmaceutical's adverse reaction profile.

22. One comment stated that the references to changes in the

physiologic or biochemical function of target and nontarget tissues and

to clinically detectable signs and symptoms should be deleted because

such events do not occur (or not to any significant extent) with

diagnostic radiopharmaceuticals.

FDA disagrees with the comment. FDA's experience with evaluating

the safety of radiopharmaceuticals has demonstrated that the

physiologic and biological function of target and nontarget tissues may

be affected by the administration of a radiopharmaceutical. For

example, as noted previously, the administration of a radiolabeled

antibody can produce a strong immune system response. Moreover, changes

in target and nontarget tissues can sometimes result in clinically

detectable signs and symptoms, such as the anaphylactoid response

discussed previously. Therefore, FDA may need information on a

radiopharmaceutical's potential to produce changes in the physiologic

or biochemical function of tissues as well as clinically detectable

signs and symptoms to accurately assess the drug's adverse reaction

profile.

23. Proposed Secs. 315.6(c)(1) and 601.35(c)(1) stated that, among

other information, FDA may require the following types of data to

establish the safety of a diagnostic radiopharmaceutical: Pharmacology

data, toxicology data, clinical adverse event data, and a radiation

safety assessment. One comment maintained that pharmacology,

toxicology, and clinical adverse event data are for the most part not

relevant due to the minute mass of the radiopharmaceutical.

FDA disagrees with the comment. Diagnostic radiopharmaceuticals

differ widely in mass, and the pharmacological and toxicological

effects of a diagnostic radiopharmaceutical are not necessarily related

to the mass of the drug product. However, the mass of a diagnostic

radiopharmaceutical may be a relevant factor in FDA's determination of

the type of pharmacology, toxicology, clinical adverse event

monitoring, and radiation safety data needed to establish the safety of

a diagnostic radiopharmaceutical.

24. Proposed Secs. 315.6(c)(2) and 601.35(c)(2) stated that the

amount of new safety data required for a diagnostic radiopharmaceutical

would depend on the characteristics of the product and available

information on the safety of the diagnostic radiopharmaceutical

obtained from other studies and uses. Included among such information

would be the dose, route of

[[Page 26664]]

administration, frequency of use, half-life of the ligand or carrier,

half-life of the radionuclide, and results of preclinical studies. FDA

would categorize diagnostic radiopharmaceuticals based on defined

characteristics relevant to risk and would specify the amount and type

of safety data appropriate for each category. For example, required

safety data would be limited for a category of radiopharmaceuticals

with a well established, low-risk profile.

One comment contended that these provisions fail to address the

possibility of a reduction in required safety data for previously

unapproved radiopharmaceuticals. The comment stated that where

preexisting data demonstrate a history of safe use of a carrier or

ligand of a diagnostic radiopharmaceutical, such information should

permit a reduction in the amount of new safety data that the sponsor

must provide. Therefore, the comment recommended that the phrase ``or

its carrier or ligand component'' be added following

``radiopharmaceutical'' in Secs. 315.6(c)(2) and 601.35(c)(2).

FDA agrees with the comment that such prior data may permit a

reduction in the amount of new safety data that a sponsor may need to

provide and has revised these sections accordingly.

25. One comment noted that ``results of preclinical studies,'' but

not clinical studies, is listed among the kinds of information on the

safety of a diagnostic radiopharmaceutical that might be used to

determine the amount of new safety data required in an application. The

comment argued that clinical information may also be important to

consider in determining what new safety data is needed. Such clinical

information could include data on a diagnostic radiopharmaceutical

approved for a different indication, on a carrier or ligand that has a

history of use as a carrier or ligand in an approved

radiopharmaceutical or as the active ingredient in a therapeutic

product, or from Phase 1 studies on the drug that is the subject of the

pending application. Although the comment recognized that the list of

information on the safety of a diagnostic radiopharmaceutical in

proposed Secs. 315.6(c)(2) and 601.35(c)(2) was not exclusive, the

comment believed that failure to explicitly include the results of

clinical studies might dissuade sponsors from providing FDA with useful

clinical information early in the clinical development program for the

drug.

FDA agrees with the comment and has revised these sections

accordingly.

26. One comment agreed with FDA's proposal to define a category of

low-risk radiopharmaceuticals that would be subject to reduced safety

requirements. The comment stated that FDA should provide in a guidance

document a description of the low-risk category, criteria for

eligibility, and types of safety data required for products in this

category. The comment contended that the medical imaging draft guidance

does not specify the different safety requirements for Group 1 and

Group 2 medical imaging drugs beyond stating that reduced safety

monitoring is appropriate for Phase 2 and 3 studies on Group 1 drugs.

FDA agrees with the comment and will consider revising the medical

imaging draft guidance to further address the type of safety

information that may be appropriate for Group 1 and Group 2 medical

imaging drugs.

27. One comment asked that proposed Secs. 315.6(c)(2) and

601.35(c)(2) be revised to clarify that, even for radiopharmaceuticals

that do not fall within a low-risk category, FDA will consider existing

information and determine on an ad hoc basis the amount of new safety

data that is required for a particular diagnostic radiopharmaceutical

product.

FDA has revised Secs. 315.6(c)(2) and 601.35(c)(2) to clarify the

agency's approach to determining the amount of new safety data that

will be required for a particular diagnostic radiopharmaceutical. As

stated in revised Secs. 315.6(c)(2) and 601.35(c)(2), FDA will consider

certain product characteristics and available safety information

obtained from other studies and uses in determining the amount of new

safety information that is needed for each drug. The information that

FDA may review includes, but is not limited to, the following: The

dose, route of administration, and frequency of use of the diagnostic

radiopharmaceutical; the half-life of the ligand, carrier, and

radionuclide; and results of clinical studies. In the medical imaging

guidance, FDA will establish categories of diagnostic

radiopharmaceuticals based on defined characteristics relevant to

safety risk and will specify the amount and type of safety data that is

appropriate for each category (e.g., required safety data may be

limited for diagnostic radiopharmaceuticals with a well established,

low-risk profile). Based on its review of the previously listed product

characteristics and safety information, FDA will place each diagnostic

radiopharmaceutical into the appropriate safety risk category.

28. One comment stated that the regulation should specify a

procedure by which a sponsor may provide FDA with information on the

basis of which the agency can categorize a diagnostic

radiopharmaceutical according to new safety data required. The comment

maintained that this would enable manufacturers to make product

development decisions with the assurance that a categorization process

will be available and applied consistently. The comment recommended

that the categorization procedure provide for the following: (1)

Sponsor submission of a request for low-risk designation at a meeting

prior to the submission of an investigational new drug application

(IND) or any subsequent time; (2) FDA designation of the product as low

risk if the sponsor submits preclinical data, clinical data, and/or

other information demonstrating that the radiopharmaceutical possesses

the characteristics of a low-risk category drug; and (3) FDA action on

a designation request within 30 days of submission.

FDA agrees that there should be a standard procedure that the

sponsor of a diagnostic radiopharmaceutical may follow to request that

the agency assign the radiopharmaceutical to a particular safety risk

category. FDA also agrees that such procedure should specify, among

other things, when a request for categorization may be made and the

information that should be submitted with a request. However, FDA

believes that it is more practical to address this matter in the

medical imaging guidance rather than in regulations.

29. One comment requested that proposed Secs. 315.6(c)(2) and

601.35(c)(2) be revised to clarify that a diagnostic

radiopharmaceutical that has not been previously approved may be

eligible for low-risk categorization. The comment noted that this would

allow low-risk categorization of a previously unapproved

radiopharmaceutical when (1) there is a history of safe use of the

radiopharmaceutical's ligand or carrier or (2) the sponsor submits

sufficient preclinical and toxicology data on the radiopharmaceutical

itself.

FDA agrees that, under Secs. 315.6(c)(2) and 601.35(c)(2), a

diagnostic radiopharmaceutical that has not been previously approved

may be eligible for placement in a low-risk category under certain

circumstances, such as those suggested by the comment. However, FDA

finds it unnecessary to revise these sections of the regulations to

specifically refer to diagnostic radiopharmaceuticals that have not

been previously approved because the rule does not address the approval

status of the radiopharmaceuticals. The agency intends to revise the

medical imaging draft guidance to clarify that even a diagnostic

radiopharmaceutical that has

[[Page 26665]]

not been previously approved may, under certain circumstances, fall

within a low-risk category.

30. Proposed Secs. 315.6(d) and 601.35(d) stated that a radiation

safety assessment would establish the radiation dose of a diagnostic

radiopharmaceutical by radiation dosimetry evaluations in humans and

appropriate animal models. In making such an evaluation, dosimetry to

the total body, to specific organs or tissues, and, if appropriate, to

target organs or tissues must be considered, although the maximum

tolerated dose need not be established.

One comment stated that a radiation safety assessment should

usually consist of an estimate of radiation absorbed dose in a few

normal subjects and that there is no need for subjects with renal or

hepatic insufficiency or other diseases. The comment maintained that

precise dosimetry is usually unnecessary, especially for Tc-99m agents,

because absorbed doses are insignificant. The comment added that even

though some radionuclides may give selected organ doses that are not

insignificant, such doses are low and have not been associated with any

hazard.

FDA does not agree that it is unnecessary to measure dosimetry and

to assess the radiation safety of a diagnostic radiopharmaceutical. FDA

agrees that current knowledge suggests that absorbed radiation doses

from some diagnostic radiopharmaceuticals are not significant. However,

as the comment notes, the experience with dosimetry and radiation

safety demonstrates that this is not true for all diagnostic

radiopharmaceuticals. Because the agency does not know the future

significance of the absorbed radiation dose of a particular diagnostic

radiopharmaceutical, current standardized dosimetry measurements are

needed for all diagnostic radiopharmaceuticals. These standardized

dosimetry measurements ensure that the absorbed radiation dose of a

particular diagnostic radiopharmaceutical is recorded in a standardized

procedure and that the current known risk of radiation injury from the

radiopharmaceutical is as low as possible.

31. There were three comments on evaluation of radiation dosimetry.

Two comments objected to the use of dosimetry to the total body because

it assumes uniform, homogenous distribution of a radiopharmaceutical

throughout the body. The comments contended that this is inaccurate

because diagnostic radiopharmaceuticals must localize in certain organs

or tissues to be clinically useful and because essentially all

diagnostic radiopharmaceuticals undergo some type of elimination from

the body that leads to concentration in the kidneys/urinary tract or

liver/biliary tract/gastrointestinal tract. The comments maintained

that because diagnostic radiopharmaceuticals are heterogeneously

concentrated in various organs and tissues having different

radiosensitivities, the radiation safety assessment should consider

radiation absorbed doses for all organs and tissues in conjunction with

their relative radiosensitivities using a so-called ``effective dose''

calculation.

FDA acknowledges that a diagnostic radiopharmaceutical is not

distributed uniformly throughout the body but rather localizes in

particular organs or tissues. Although FDA agrees that effective dose

is a relevant measure of dosimetry, the measurement of total body

dosimetry also may provide relevant information in some settings. FDA

believes that each sponsor should use dosimetry measurements that are

appropriate for a particular diagnostic radiopharmaceutical in the

defined clinical setting, whether this requires measurement of

dosimetry to the total body, to specific organs or tissues, and/or to

target organs or tissues. However, FDA concludes that it is more

appropriate to address this matter in the medical imaging guidance

rather than the regulations so that dosimetry evaluations of diagnostic

radiopharmaceuticals may better reflect developments in

radiopharmaceutical science. Consequently, the agency is deleting the

sentence in proposed Secs. 315.6(d) and 601.35(d) specifying what must

be considered in a radiation dosimetry evaluation.

32. A third comment on evaluation of radiation dosimetry noted that

the ``Guideline for the Clinical Evaluation of Radiopharmaceutical

Drugs'' states that organ and tissue dosimetries are required only in

preclinical studies; for clinical studies, dosimetry calculations

should be made only on the primary organ(s) of interest and should

follow the system specified by the Medical Internal Radiation Dose

Committee of the Society of Nuclear Medicine. The comment recommended

that the final rule include similar recommendations. The comment also

maintained that the final rule must distinguish preclinical from

clinical expectations.

FDA believes that the appropriate design of the preclinical and

clinical dosimetry studies for determining radiation dosimetry must be

based on the characteristics of the radiopharmaceutical, e.g.,

biodistribution, pharmacological actions, and clearance pathways. FDA

intends to address in the medical imaging guidance the preclinical and

clinical dosimetry measurements that are considered currently

appropriate for different types of diagnostic radiopharmaceuticals.

Therefore, FDA declines to include in the regulations specific methods

or models of dosimetry or to distinguish between the preclinical and

clinical dosimetry requirements in the regulations.

33. There were two comments on maximum tolerated dose. One comment

found the statement that the maximum tolerated dose need not be

established to be ``curious'' because the maximum tolerated radiation

dose was established decades ago. One comment asked that FDA clarify

whether the phrase refers to the maximum tolerated dose associated with

adverse events and laboratory abnormalities or to the maximum tolerated

dose based on radiation dosimetry.

By stating in Secs. 315.6(d) and 601.35(d) that the maximum

tolerated dose need not be established, FDA is simply clarifying that

there is no need to determine the maximum tolerated dose of radiation

as part of the radiation dosimetry evaluation.

IV. Analysis of Economic Impacts

FDA has examined the impact of the final rule under Executive Order

12866, under the Regulatory Flexibility Act (5 U.S.C. 601-612), and

under the Unfunded Mandates Reform Act (Pub. L. 104-4). Executive Order

12866 directs agencies to assess all costs and benefits of available

regulatory approaches that maximize net benefits (including potential

economic, environmental, public health and safety, and other

advantages; distributive impacts; and equity). Under the Regulatory

Flexibility Act, unless an agency certifies that a rule will not have a

significant economic impact on a substantial number of small entities,

the agency must analyze significant regulatory options that would

minimize any significant economic impact of a rule on small entities.

The Unfunded Mandates Reform Act requires (in section 202) that

agencies prepare an assessment of anticipated costs and benefits before

proposing any mandate that results in an expenditure by State, local,

and tribal governments, in the aggregate, or by the private sector, of

$100 million in any 1 year.

The agency has reviewed this final rule and has determined that it

is consistent with the principles set forth in the Executive Order and

in these two statutes. FDA finds that, while the rule

[[Page 26666]]

will not be an economically significant rule, it is a significant

regulatory action as described in section 3 paragraph (f)(4) of the

Executive Order. Further, the agency finds that, under the Regulatory

Flexibility Act, the rule will not have a significant economic impact

on a substantial number of small entities. Also, since the expenditures

resulting from the standards identified in the rule are less than $100

million, FDA is not required to perform a cost/benefit analysis

according to the Unfunded Mandates Reform Act.

The final rule clarifies existing FDA requirements for the approval

and evaluation of drug and biological products already in place under

the act and the PHS Act. Existing regulations (parts 314 and 601)

specify the type of information that manufacturers are required to

submit so that the agency may properly evaluate the safety and

effectiveness of new drugs or biological products. Such information is

usually submitted as part of an NDA, BLA, or supplement to an approved

application. The information typically includes both nonclinical and

clinical data concerning the product's pharmacology, toxicology,

adverse events, radiation safety assessments, chemistry, and

manufacturing and controls. The final regulation recognizes the unique

characteristics of diagnostic radiopharmaceuticals and sets out the

agency's approach to the evaluation of these products. For certain

diagnostic radiopharmaceuticals, the final regulation may reduce the

amount of safety information that an applicant must obtain by

conducting new clinical studies. This would include approved

radiopharmaceuticals with well established, low-risk safety profiles

because such products might be able to use scientifically sound data

established during use of the radiopharmaceutical to support the

approval of a new indication for use. In addition, the clarification

achieved by the final rule is expected to reduce the costs of

submitting an application for approval of a diagnostic

radiopharmaceutical by improving communications between applicants and

the agency and by reducing wasted effort directed toward the submission

of data that is not necessary to meet the statutory approval standard.

Manufacturers of diagnostic radiopharmaceuticals are defined by the

Small Business Administration as small businesses if such manufacturers

employ fewer than 500 employees. The agency finds that only 2 of the 8

companies that currently manufacture or market radiopharmaceuticals

have fewer than 500 employees.\1\ Moreover, the final rule would not

impose any additional costs but, rather, might reduce the clinical

costs associated with the existing regulations by clarifying data

submission requirements. One comment stated that the regulatory costs

currently associated with developing new radiopharmaceuticals have made

it difficult for more than two small entities to stay in business.

While the agency is not aware of any safe and effective

radiopharmaceuticals that have been prevented from entering the

marketplace, it believes that this rule might reduce costs and

therefore benefit small entities. Therefore, in accordance with the

Regulatory Flexibility Act, FDA certifies that this rule will not have

a significant economic impact on a substantial number of small

entities.

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\1\ Medical & Healthcare Marketplace Guide, 13th ed., Dorland's

Directories, 1997.

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V. The Paperwork Reduction Act of 1995

This final rule contains information collection provisions that are

subject to review by the Office of Management and Budget (OMB) under

the Paperwork Reduction Act of 1995 (PRA) (44 U.S.C. 3501-3520). The

title, description, and the respondent description of the information

collection provisions are shown below with an estimate of the annual

reporting burden. Included in the estimate is the time for reviewing

the instructions, searching existing data sources, gathering and

maintaining the data needed, and completing and reviewing each

collection of information.

Title: Regulations for In Vivo Radiopharmaceuticals Used for

Diagnosis and Monitoring.

Description: FDA is finalizing regulations for the evaluation and

approval of in vivo radiopharmaceuticals used for diagnosis and

monitoring. The final rule clarifies existing FDA requirements for

approval and evaluation of drug and biological products already in

place under the authorities of the act and the PHS Act. Those

regulations, which appear primarily in parts 314 and 601, specify the

information that manufacturers must submit to FDA for the agency to

properly evaluate the safety and effectiveness of new drugs or

biological products. The information, which is usually submitted as

part of an NDA or BLA, or as a supplement to an approved application,

typically includes, but is not limited to, nonclinical and clinical

data on the pharmacology, toxicology, adverse events, radiation safety

assessments, and chemistry, manufacturing, and controls. The content

and format of an application for approval of a new drug are set out in

Sec. 314.50 and for a new biological product in Sec. 601.2. Under part

315 and Secs. 601.30 through 601.35 of part 601, information required

under the act and the PHS Act, and needed by FDA to evaluate the safety

and effectiveness of in vivo radiopharmaceuticals, will still need to

be reported.

Description of Respondents: Manufacturers of in vivo

radiopharmaceuticals used for diagnosis and monitoring.

As required by section 3506 (c)(2)(B) of the PRA, FDA provided an

opportunity for public comment on May 22, 1998 (63 FR 28301), on the

information collection provisions of the proposed rule. FDA received

one comment on the information collection provisions. The comment

stated that use of the figure of seven approved diagnostic

radiopharmaceuticals in fiscal year 1997 (FY 1997) resulted in a very

low estimate of the expected number of future annual applications. The

comment suggested that 50 applications would be a more appropriate

figure.

Based on 5 years of experience, FDA believes that the estimate of

the number of applications for approval of in vivo diagnostic

radiopharmaceuticals is a reasonable one. In FY 1992 to 1997, FDA

approved 13 in vivo diagnostic radiopharmaceuticals. In FY 1998, only

one such product was approved. The agency does not expect an increase

in applications for approval of diagnostic radiopharmaceuticals in the

near future. Although sponsors may submit higher numbers of IND's for

diagnostic radiopharmaceuticals each year, the annual number of NDA's,

abbreviated new drug applications, and BLA's approved is small. FDA

therefore declines to change its estimate.

In a notice of action on the proposed rule dated July 17, 1998, OMB

stated that it had concerns about the utility and burden of the

information collected to demonstrate the safety and effectiveness of a

new diagnostic radiopharmaceutical or of a new indication for use of an

approved diagnostic radiopharmaceutical. OMB maintained that the burden

and utility of this information collection should be assessed in light

of public comments on the proposed rule and that FDA should

specifically address such comments in the preamble to the final rule.

Section 122 of the Modernization Act directs FDA to develop

regulations on the approval of diagnostic radiopharmaceuticals under

section 505 of the act. As discussed previously, FDA

[[Page 26667]]

received only one comment on the information collection provisions of

the proposed rule. None of the manufacturers of diagnostic

radiopharmaceuticals who submitted comments on the proposed rule

questioned the need for the submission of information to demonstrate

the safety and effectiveness of a product to obtain marketing approval.

Rather, their comments primarily sought clarification or proposed minor

modification of the proposed regulations.

To estimate the potential number of respondents that would submit

applications or supplements for diagnostic radiopharmaceuticals, FDA

used the number of approvals granted in FY 1997 to approximate the

number of future annual applications. In FY 1997, FDA approved seven

diagnostic radiopharmaceuticals and received one new indication

supplement; of these, three respondents received approval through the

Center for Drug Evaluation and Research and five received approval

through the Center for Biologics Evaluation and Research. The annual

frequency of responses was estimated to be one response per application

or supplement. The hours per response refers to the estimated number of

hours that an applicant would spend preparing the information required

by the final regulations. Based on FDA's experience, the agency

estimates the time needed to prepare a complete application for a

diagnostic radiopharmaceutical to be approximately 10,000 hours,

roughly one-fifth of which, or 2,000 hours, is estimated to be spent

preparing the portions of the application that are affected by these

final regulations. The final rule would not impose any additional

reporting burden for safety and effectiveness information on diagnostic

radiopharmaceuticals beyond the estimated current burden of 2,000 hours

because safety and effectiveness information is already required by

Sec. 314.50 under OMB control number 0910-0001 and Sec. 601.2 under OMB

control number 0910-0124. In fact, clarification in the final rule of

FDA's standards for evaluation of diagnostic radiopharmaceuticals is

expected to streamline overall information collection burdens,

particularly for diagnostic radiopharmaceuticals that may have well

established, low-risk safety profiles, by enabling manufacturers to

tailor information submissions and avoid conducting unnecessary

clinical studies. The following table indicates estimates of the annual

reporting burdens for the preparation of the safety and effectiveness

sections of an application that are imposed by existing regulations,

Secs. 314.50 and 601.2. The burden totals do not include an increase in

burden because no increase is anticipated. This estimate does not

include the actual time needed to conduct studies and trials or other

research from which the reported information is obtained.

Table 1.--Estimated Annual Reporting Burden\1\

----------------------------------------------------------------------------------------------------------------

Annual

21 CFR Section No. of Frequency per Total Annual Hours per Total Hours

Respondents Response Responses Response

----------------------------------------------------------------------------------------------------------------

315.4, 315.5, and 315.6 3 1 3 2,000 6,000

601.33, 601.34, and 601.35 5 1 5 2,000 10,000

Total 8 8 16,000

----------------------------------------------------------------------------------------------------------------

\1\ There are no capital costs or operating and maintenance costs associated with this collection of

information.

The information collection provisions of the final rule have been

submitted to OMB for review. Prior to the effective date of the final

rule, FDA will publish a notice in the Federal Register announcing

OMB's decision to approve, modify, or disapprove the information

collection provisions in the final rule. An agency may not conduct or

sponsor, and a person is not required to respond to, a collection of

information unless it displays a currently valid OMB control number.

VI. Environmental Impact

The agency has determined under 21 CFR 25.30(h) that this action is

of a type that does not individually or cumulatively have a significant

effect on the human environment. Therefore, neither an environmental

assessment nor an environmental impact statement is required.

List of Subjects

21 CFR Part 315

Biologics, Diagnostic radiopharmaceuticals, Drugs.

21 CFR Part 601

Administrative practice and procedure, Biologics, Confidential

business information.

Therefore, under the Federal Food, Drug, and Cosmetic Act, the

Public Health Service Act, the Food and Drug Administration

Modernization Act, and under authority delegated to the Commissioner of

Food and Drugs, 21 CFR chapter I is amended to read as follows:

1. Part 315 is added to read as follows:

PART 315--DIAGNOSTIC RADIOPHARMACEUTICALS

Sec.

315.1 Scope.

315.2 Definition.

315.3 General factors relevant to safety and effectiveness.

315.4 Indications.

315.5 Evaluation of effectiveness.

315.6 Evaluation of safety.

Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 371, 374,

379e; sec. 122, Pub. L. 105-115, 111 Stat. 2322 (21 U.S.C. 355

note).

Sec. 315.1 Scope.

The regulations in this part apply to radiopharmaceuticals intended

for in vivo administration for diagnostic and monitoring use. They do

not apply to radiopharmaceuticals intended for therapeutic purposes. In

situations where a particular radiopharmaceutical is proposed for both

diagnostic and therapeutic uses, the radiopharmaceutical must be

evaluated taking into account each intended use.

Sec. 315.2 Definition.

For purposes of this part, diagnostic radiopharmaceutical means:

(a) An article that is intended for use in the diagnosis or

monitoring of a disease or a manifestation of a disease in humans and

that exhibits spontaneous disintegration of unstable nuclei with the

emission of nuclear particles or photons; or

(b) Any nonradioactive reagent kit or nuclide generator that is

intended to be used in the preparation of such article as defined in

paragraph (a) of this section.

[[Page 26668]]

Sec. 315.3 General factors relevant to safety and effectiveness.

FDA's determination of the safety and effectiveness of a diagnostic

radiopharmaceutical includes consideration of the following:

(a) The proposed use of the diagnostic radiopharmaceutical in the

practice of medicine,

(b) The pharmacological and toxicological activity of the

diagnostic radiopharmaceutical (including any carrier or ligand

component of the diagnostic radiopharmaceutical), and

(c) The estimated absorbed radiation dose of the diagnostic

radiopharmaceutical.

Sec. 315.4 Indications.

(a) For diagnostic radiopharmaceuticals, the categories of proposed

indications for use include, but are not limited to, the following:

(1) Structure delineation;

(2) Functional, physiological, or biochemical assessment;

(3) Disease or pathology detection or assessment; and

(4) Diagnostic or therapeutic patient management.

(b) Where a diagnostic radiopharmaceutical is not intended to

provide disease-specific information, the proposed indications for use

may refer to a biochemical, physiological, anatomical, or pathological

process or to more than one disease or condition.

Sec. 315.5 Evaluation of effectiveness.

(a) The effectiveness of a diagnostic radiopharmaceutical is

assessed by evaluating its ability to provide useful clinical

information related to its proposed indications for use. The method of

this evaluation varies depending upon the proposed indication(s) and

may use one or more of the following criteria:

(1) The claim of structure delineation is established by

demonstrating in a defined clinical setting the ability to locate

anatomical structures and to characterize their anatomy.

(2) The claim of functional, physiological, or biochemical

assessment is established by demonstrating in a defined clinical

setting reliable measurement of function(s) or physiological,

biochemical, or molecular process(es).

(3) The claim of disease or pathology detection or assessment is

established by demonstrating in a defined clinical setting that the

diagnostic radiopharmaceutical has sufficient accuracy in identifying

or characterizing the disease or pathology.

(4) The claim of diagnostic or therapeutic patient management is

established by demonstrating in a defined clinical setting that the

test is useful in diagnostic or therapeutic patient management.

(5) For a claim that does not fall within the indication categories

identified in Sec. 315.4, the applicant or sponsor should consult FDA

on how to establish the effectiveness of the diagnostic

radiopharmaceutical for the claim.

(b) The accuracy and usefulness of the diagnostic information is

determined by comparison with a reliable assessment of actual clinical

status. A reliable assessment of actual clinical status may be provided

by a diagnostic standard or standards of demonstrated accuracy. In the

absence of such diagnostic standard(s), the actual clinical status must

be established in another manner, e.g., patient followup.

Sec. 315.6 Evaluation of safety.

(a) Factors considered in the safety assessment of a diagnostic

radiopharmaceutical include, among others, the following:

(1) The radiation dose;

(2) The pharmacology and toxicology of the radiopharmaceutical,

including any radionuclide, carrier, or ligand;

(3) The risks of an incorrect diagnostic determination;

(4) The adverse reaction profile of the drug;

(5) Results of human experience with the radiopharmaceutical for

other uses; and

(6) Results of any previous human experience with the carrier or

ligand of the radiopharmaceutical when the same chemical entity as the

carrier or ligand has been used in a previously studied product.

(b) The assessment of the adverse reaction profile includes, but is

not limited to, an evaluation of the potential of the diagnostic

radiopharmaceutical, including the carrier or ligand, to elicit the

following:

(1) Allergic or hypersensitivity responses,

(2) Immunologic responses,

(3) Changes in the physiologic or biochemical function of the

target and nontarget tissues, and

(4) Clinically detectable signs or symptoms.

(c)(1) To establish the safety of a diagnostic radiopharmaceutical,

FDA may require, among other information, the following types of data:

(i) Pharmacology data,

(ii) Toxicology data,

(iii) Clinical adverse event data, and

(iv) Radiation safety assessment.

(2) The amount of new safety data required will depend on the

characteristics of the product and available information regarding the

safety of the diagnostic radiopharmaceutical, and its carrier or

ligand, obtained from other studies and uses. Such information may

include, but is not limited to, the dose, route of administration,

frequency of use, half-life of the ligand or carrier, half-life of the

radionuclide, and results of clinical and preclinical studies. FDA will

establish categories of diagnostic radiopharmaceuticals based on

defined characteristics relevant to risk and will specify the amount

and type of safety data that are appropriate for each category (e.g.,

required safety data may be limited for diagnostic radiopharmaceuticals

with a well established, low-risk profile). Upon reviewing the relevant

product characteristics and safety information, FDA will place each

diagnostic radiopharmaceutical into the appropriate safety risk

category.

(d) Radiation safety assessment. The radiation safety assessment

must establish the radiation dose of a diagnostic radiopharmaceutical

by radiation dosimetry evaluations in humans and appropriate animal

models. The maximum tolerated dose need not be established.

PART 601--LICENSING

2. The authority citation for part 601 is revised to read as

follows:

Authority: 15 U.S.C. 1451-1561; 21 U.S.C. 321, 351, 352, 353,

355, 360, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C. 216,

241, 262, 263; sec. 122, Pub. L. 105-115, 111 Stat. 2322 (21 U.S.C.

355 note).

Sec. 601.33 [Redesignated as Sec. 601.28]

3. Section 601.33 is redesignated as Sec. 601.28 and transferred

from subpart D to subpart C, and the redesignated section heading is

revised to read as follows:

Sec. 601.28 Foreign establishments and products: samples for each

importation.

* * * * *

4. Subpart D is revised to read as follows:

Subpart D--Diagnostic Radiopharmaceuticals

Sec.

601.30 Scope.

601.31 Definition.

601.32 General factors relevant to safety and effectiveness.

601.33 Indications.

601.34 Evaluation of effectiveness.

601.35 Evaluation of safety.

[[Page 26669]]

Subpart D--Diagnostic Radiopharmaceuticals

Sec. 601.30 Scope.

This subpart applies to radiopharmaceuticals intended for in vivo

administration for diagnostic and monitoring use. It does not apply to

radiopharmaceuticals intended for therapeutic purposes. In situations

where a particular radiopharmaceutical is proposed for both diagnostic

and therapeutic uses, the radiopharmaceutical must be evaluated taking

into account each intended use.

Sec. 601.31 Definition.

For purposes of this part, diagnostic radiopharmaceutical means:

(a) An article that is intended for use in the diagnosis or

monitoring of a disease or a manifestation of a disease in humans and

that exhibits spontaneous disintegration of unstable nuclei with the

emission of nuclear particles or photons; or

(b) Any nonradioactive reagent kit or nuclide generator that is

intended to be used in the preparation of such article as defined in

paragraph (a) of this section.

Sec. 601.32 General factors relevant to safety and effectiveness.

FDA's determination of the safety and effectiveness of a diagnostic

radiopharmaceutical includes consideration of the following:

(a) The proposed use of the diagnostic radiopharmaceutical in the

practice of medicine;

(b) The pharmacological and toxicological activity of the

diagnostic radiopharmaceutical (including any carrier or ligand

component of the diagnostic radiopharmaceutical); and

(c) The estimated absorbed radiation dose of the diagnostic

radiopharmaceutical.

Sec. 601.33 Indications.

(a) For diagnostic radiopharmaceuticals, the categories of proposed

indications for use include, but are not limited to, the following:

(1) Structure delineation;

(2) Functional, physiological, or biochemical assessment;

(3) Disease or pathology detection or assessment; and

(4) Diagnostic or therapeutic patient management.

(b) Where a diagnostic radiopharmaceutical is not intended to

provide disease-specific information, the proposed indications for use

may refer to a biochemical, physiological, anatomical, or pathological

process or to more than one disease or condition.

Sec. 601.34 Evaluation of effectiveness.

(a) The effectiveness of a diagnostic radiopharmaceutical is

assessed by evaluating its ability to provide useful clinical

information related to its proposed indications for use. The method of

this evaluation varies depending upon the proposed indication(s) and

may use one or more of the following criteria:

(1) The claim of structure delineation is established by

demonstrating in a defined clinical setting the ability to locate

anatomical structures and to characterize their anatomy.

(2) The claim of functional, physiological, or biochemical

assessment is established by demonstrating in a defined clinical

setting reliable measurement of function(s) or physiological,

biochemical, or molecular process(es).

(3) The claim of disease or pathology detection or assessment is

established by demonstrating in a defined clinical setting that the

diagnostic radiopharmaceutical has sufficient accuracy in identifying

or characterizing the disease or pathology.

(4) The claim of diagnostic or therapeutic patient management is

established by demonstrating in a defined clinical setting that the

test is useful in diagnostic or therapeutic patient management.

(5) For a claim that does not fall within the indication categories

identified in Sec. 601.33, the applicant or sponsor should consult FDA

on how to establish the effectiveness of the diagnostic

radiopharmaceutical for the claim.

(b) The accuracy and usefulness of the diagnostic information is

determined by comparison with a reliable assessment of actual clinical

status. A reliable assessment of actual clinical status may be provided

by a diagnostic standard or standards of demonstrated accuracy. In the

absence of such diagnostic standard(s), the actual clinical status must

be established in another manner, e.g., patient followup.

Sec. 601.35 Evaluation of safety.

(a) Factors considered in the safety assessment of a diagnostic

radiopharmaceutical include, among others, the following:

(1) The radiation dose;

(2) The pharmacology and toxicology of the radiopharmaceutical,

including any radionuclide, carrier, or ligand;

(3) The risks of an incorrect diagnostic determination;

(4) The adverse reaction profile of the drug;

(5) Results of human experience with the radiopharmaceutical for

other uses; and

(6) Results of any previous human experience with the carrier or

ligand of the radiopharmaceutical when the same chemical entity as the

carrier or ligand has been used in a previously studied product.

(b) The assessment of the adverse reaction profile includes, but is

not limited to, an evaluation of the potential of the diagnostic

radiopharmaceutical, including the carrier or ligand, to elicit the

following:

(1) Allergic or hypersensitivity responses,

(2) Immunologic responses,

(3) Changes in the physiologic or biochemical function of the

target and nontarget tissues, and

(4) Clinically detectable signs or symptoms.

(c)(1) To establish the safety of a diagnostic radiopharmaceutical,

FDA may require, among other information, the following types of data:

(A) Pharmacology data,

(B) Toxicology data,

(C) Clinical adverse event data, and

(D) Radiation safety assessment.

(2) The amount of new safety data required will depend on the

characteristics of the product and available information regarding the

safety of the diagnostic radiopharmaceutical, and its carrier or

ligand, obtained from other studies and uses. Such information may

include, but is not limited to, the dose, route of administration,

frequency of use, half-life of the ligand or carrier, half-life of the

radionuclide, and results of clinical and preclinical studies. FDA will

establish categories of diagnostic radiopharmaceuticals based on

defined characteristics relevant to risk and will specify the amount

and type of safety data that are appropriate for each category (e.g.,

required safety data may be limited for diagnostic radiopharmaceuticals

with a well established, low-risk profile). Upon reviewing the relevant

product characteristics and safety information, FDA will place each

diagnostic radiopharmaceutical into the appropriate safety risk

category.

(d) Radiation safety assessment. The radiation safety assessment

must establish the radiation dose of a diagnostic radiopharmaceutical

by radiation dosimetry evaluations in humans and appropriate animal

models. The maximum tolerated dose need not be established.

[[Page 26670]]

Dated: April 16, 1999.

William K. Hubbard,

Associate Commissioner for Policy Coordination.

[FR Doc. 99-12320 Filed 5-14-99; 8:45 am]

BILLING CODE 4160-01-F